Kymriah · 4.4 Special warnings and precautions for use · 1

HOS-097637 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile Safety assessment was based on a total of 424 patients (with paediatric and young adult B-cell ALL, DLBCL and FL) who received Kymriah in three multicentre pivotal clinical studies. B-cell ALL The adverse reactions described in this section were characterised in 212 patients infused with Kymriah in the pivotal clinical study CCTL019B2202 and in the supportive studies CCTL019B2205J and CCTL019B2001X. The most common non-haematological adverse reactions were cytokine release syndrome (75%), infections (70%), hypogammaglobulinaemia (49%), pyrexia (43%) and decreased appetite (28%). The most common haematological laboratory abnormalities were decreased white blood cells (100%), decreased haemoglobin (99%), decreased neutrophils (98%), decreased lymphocytes (98%) and decreased platelets (95%). Grade 3 and 4 adverse reactions were reported in 86% of patients. The most common Grade 3 and 4 non-haematological adverse reaction was cytokine release syndrome (37%). The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cells decreased (97%), lymphocytes decreased (94%), neutrophils decreased (96%), platelets decreased (70%) and haemoglobin decreased (46%). Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion (78% of patients) compared to after 8 weeks post infusion (49% of patients). DLBCL The adverse reactions described in this section were characterised in 115 patients infused with Kymriah in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019C2201. The most common non-haematological adverse reactions were cytokine release syndrome (57%), infections (58%), pyrexia (35%), diarrhoea (31%), nausea (29%), fatigue (27%) and hypotension (25%). The most common haematological laboratory abnormalities were decreased lymphocytes (100%), decreased white blood cells (99%), decreased haemoglobin (99%), decreased neutrophils (97%), and decreased platelets (95%). Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common Grade 3 and 4 non-haematological adverse reactions were infections (34%) and cytokine release syndrome (23%). The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte 11 count decreased (95%), neutrophil count decreased (82%), white blood cell count decreased (78%), haemoglobin decreased (59%) and

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HOS-097633 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4). Contraindications of the lymphodepleting chemotherapy must be considered.

HOS-097632 · has-indication-information · PDF-Seite 3

Kymriah is indicated for the treatment of: • Paediatric and young adult patients up to and including 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse. • Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. • Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

HOS-097635 · has-interaction-information · PDF-Seite 10

No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been performed in either the paediatric or adult population. The co-administration of agents known to inhibit T-cell function has not been formally studied. Administration of low-dose steroids as per the cytokine release syndrome treatment algorithm does not impact the expansion and persistence of CAR-T cells. The co-administration of agents known to stimulate T-cell function has not been investigated and the effects are unknown. Live vaccines The safety of immunisation with live vaccines during or following Kymriah treatment has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment.

HOS-097636 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception in males and females Pregnancy status for females of childbearing age should be verified prior to starting treatment with Kymriah. See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Kymriah. Pregnancy There are no data from the use of tisagenlecleucel in pregnant women. No animal studies have been conducted with tisagenlecleucel to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3). It is not known whether tisagenlecleucel has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B-cell lymphocytopenia. Kymriah is not recommended during pregnancy and in women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Kymriah therapy should be discussed with the treating physician. Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah. Breast-feeding It is unknown whether tisagenlecleucel cells are excreted in human milk. A risk to the breast-fed infant cannot be excluded. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant. Following administration of Kymriah, breast-feeding should be discussed with the treating physician. Fertility There are no data on the effect of Kymriah on fertility. Effects of Kymriah on male and female fertility 10 have not been evaluated in animal studies.

HOS-097634 · has-warning-information · PDF-Seite 5

Traceability The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the medicinal product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the medicinal product. 5 Autologous use Kymriah is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Kymriah must not be administered if the information on the product labels and batch specific documentation do not match the patient’s identity. Reasons to delay treatment Due to the risks associated with tisagenlecleucel treatment, infusion should be delayed if a patient has any of the following conditions: - Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies. - Active uncontrolled infection. - Active graft-versus-host disease (GVHD). - Significant clinical worsening of leukaemia burden or rapid progression of lymphoma following lymphodepleting chemotherapy. Transmission of an infectious agent Although Kymriah is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Kymriah must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed. Blood, organ, tissue and cell donation Patients treated with Kymriah must not donate blood, organs, tissues or cells for transplantation. This information is provided in the Patient Alert Card which should be given to the patient after treatment. Active central nervous system (CNS) leukaemia or lymphoma There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore, the risk/benefit of Kymriah has not been established in these populations. Cytokine release syndrome Cytokine release syndrome (CRS), including fatal or life-threatening events, has been frequently observed after Kymriah infusion (see section 4.8). In almost all cases, development of CRS occurred between 1 to 10 days (median onset 3 days) after Kymriah infusion in paediatric and young adult B- cell ALL patients, between 1 and 9 days (median onset 3 days) after Kymriah infusion in adult DLBCL patients and between 1 to 14 days (median onset 4 days) after Kymriah infusion in adul

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